Polyazamacrocycles and their metal complexes and oxidations using same

ABSTRACT

A 13 or 14 member macrocyclic compound having the following ring nucleus: ##STR1## wherein: n=0 or 1; 
     m=0 or 1; 
     n+m&gt;0; 
     X 1 , X 2 , Z 1  and Z 2  independently represent H 2  or O; 
     Y 1 , Y 2 , Y 3  and Y 4  independently represent H, lower alkyl or CH 2  COOH; 
     L 1  and L 2  independently represent side chains of alpha amino acids, except that L 1  and L 2  do not both represent H; and 
     R 1  and R 2  independently represent H or OH forms stable complexes with transition metal ions that may be used as catalysts for oxidizing alkenes to epoxides with oxidizing agents. 
     A method is also provided for oxidizing alkenes to epoxides by treating the alkene with a transition metal ion complex which includes the 13 or 14 member macrocyclic compound of the invention, a cyclam or a Schiff base complex and peroxymonosulfate ion or hypochlorite ion in a two phase system comprising a phase transfer catalyst, a water phase having a pH from about 6 to about 14 and an inorganic solvent phase in which the complex is sufficiently soluble.

This work was supported by grants from the National Institutes of Health(GM-34841) and the National Science Foundation (CHE-8706616).

This is a division of application Ser. No. 07/484,102 filed Feb. 23,1990, now U.S. Pat. No. 4,987,227, which was a continuation-in-part ofapplication Ser. No. 07/261,032 filed Oct. 21, 1988, now abandoned.

The present invention is directed to transition metal-catalyzed transferof oxygen atoms to organic substrates. In addition, the invention isdirected to substituted polyazamacrocycles having 13 and 14 memberedrings that are easily prepared from amino acids, and the transitionmetal complexes of such polyazamacrocycles. The polyazamacrocyclecomplexes or Schiff base complexes may be used in the rapid conversionof alkenes to epoxides at a high turnover rate under certain novel phasetransfer conditions.

Polyhetero atom macrocycles have been extensively studied, especiallywith respect to their ability to form complexes with metal ions. A goodexample of such polyhetero macrocycles are the polyethers, which readilyform complexes with alkali and alkaline earth metals.

Polyazamacrocycles have been investigated due to their ability to formcomplexes with transition metal ions. A typical polyazamacrocyclecapable of complexing transition metal ions is1,4,8,11-tetraazacyclotetradecane (cyclam). Cyclam has structure 1. Theability of cyclam and its derivatives to form stable complexes withcobalt, nickel, copper and other metal ions and to stabilize highoxidation states of these metals has recently been studied (Busch, Acc.Chem. Res. 11, 392-400 (1978)). ##STR2##

More recently, 1,4,8,11-tetraazacyclotetradecane-5,7-dione (dioxocyclam)has been developed and its ability to form complexes with a limitednumber of metal ions studied. These complexes involve the coordinationof the metal ions to a deprotonated ligand. The structure of dioxocyclamis shown as structure 2. ##STR3## and the structure of the nickelcomplex of dioxocyclam is shown as structure 3. ##STR4##

In addition to the utilities mentioned above, certain complexes oftransition metal ions, such as the square planar complexes of Ni²⁺, havebeen shown to catalyze the transfer of oxygen atoms to alkenes. Epoxidesare the principal products of these reactions. Ligands used in thecomplexes for these reactions have included cyclam,N,N'-ethylene-bis(salicylideneamine), also known as salen andtrans-1,2-diaminocyclohexane, also known as salophen. The structure ofNi(salen) is shown as structure 4. ##STR5##

The structure of Ni(salophen) is shown as structure 5. ##STR6##

Relatively strong oxidizing agents, such as iodosylbenzene andhypochlorite ion, are required to oxidize alkenes to epoxides underthese conditions. The success of the reactions depend in part on thesolubility of the alkene, the oxidizing agent and the catalytic metalcomplex in the solvent in which the reaction is conducted The problem offinding a suitable reaction medium was solved by Yoon and Burrows forthe oxidation of alkenes with sodium hypochlorite and salen byconducting the reaction under phase transfer conditions; theseresearchers also described catalysis of alkene oxidation by structures1, 4 and 5 using NaOCl at pH 13 under phase transfer conditions (Yoonand Burrows, J. Am. Chem. Soc. 110, 4087-4089 (1988)). The article at J.Am. Chem. Soc. 110, 4087-4089 (1988) is incorporated by reference hereinin its entirety. The catalyst for phase transfer reactions may also bemanganese porphyrins (Meunier et al., J. Am. Chem. Soc., 106, 6668-6676(1984)).

Complexes of Schiff base derivatives such as Ni(salen) were used forolefin expoxidation with iodosylbenzene in very large excess as theterminal oxidant by Koola et al., Inorg Chem. 26, 908-16 (1987).

It has now been discovered that the rate of epoxidation when using thecyclam, dioxocyclam or Schiff base transition metal complexes isdramatically influenced by pH.

These reactions also generally suffer from a lack of flexibility inadjusting the solubility of the metal ion complex in the organicreaction media useful for organic reactions. Various substituent groupsincluding alkyl groups have been introduced into the three carbon bridgeof the cyclam and dioxocyclam ring systems. See Kimura, et al., Inorg.Chem. 1984, 23, 4181-4188; Kimura, et al., J. Am. Chem. Soc. 1984, 106,5497-5505; Kushi, et al., J. Chem. Soc., Chem. Commun 1985, 216-218;Machida, et al., Inorg. Chem. 1986, 25, 3461-3466; Kimura, et al., J.Am. Chem. Soc. 1988, 110, 3679-3680 and Tabushi, et al., TetrahedronLett. 1977, 18, 1049-1052. Such compounds, however, do not alwaysprovide the necessary flexibility and are not always sufficiently easyto make in order to be practical for commercial purposes.

Moreover, a substituent in the two carbon bridge of the cyclam anddioxocyclam ring system would be closer to the site of the reaction,which is believed to occur when the complexed metal transports an oxygenatom to the alkene. When the substituents in the two carbon bridge areon chiral carbon atoms, the possibility exists that a resulting epoxidealso having a chiral carbon atom would be optically active. Suchasymmetric induction would be useful in the synthesis of opticallyactive compounds.

There is, therefore, a need for a new class of easily synthesizedpolyazamacrocycles having a range of solubilities in media suitable forthe oxidation of alkenes to epoxides. It would, furthermore, bedesirable for such compounds to have substituents at an asymmetriccarbon atom.

OBJECTS OF THE INVENTION

It is an object of the invention to provide rapid chemical reactions foroxidizing alkenes to epoxides in high yield.

It is an additional object of the present invention to provide 13 and 14member polyazamacrocycles capable of forming stable complexes withtransition metal ions.

It is a further object of the present invention to provide complexes of13 and 14 member rings and transition metal ions capable of oxidizingalkenes to epoxides.

It is also an object of the present invention to provide 13 and 14member polyazamacrocycles capable of forming complexes with transitionmetal ions for sequestration, biomimetic catalysis and biomedicalapplications.

SUMMARY OF THE INVENTION

These and other objectives as will be apparent to those with ordinaryskill in the art have been achieved by providing a 13 or 14 membermacrocyclic ring nucleus having the structure: ##STR7## wherein: n=0 or1;

m=0 or 1;

n+m>0;

X₁, X₂, Z₁ and Z₂ independently represent H₂ or 0;

Y₁, Y₂, Y₃ and Y₄ independently represent H, lower alkyl or CH₂ COOH;

L₁ and L₂ represent side chains derived from alpha amino acids, exceptthat L₁ and L₂ do not both represent H; and

R₁ and R₂ independently represent H or OH.

The ring nucleus having structure IA or IB forms stable complexes withtransition metals, and may be used to oxidize alkenes to epoxides.

In a method for oxidizing alkenes to epoxides, the alkene is treatedwith a transition metal complex and an oxidizing agent in a two phasesystem including a phase transfer catalyst. A water phase has a pH lessthan 12.9, and the system also includes an organic solvent phase inwhich the complex is sufficiently soluble.

For a better understanding of the present invention, together with otherand further objects, reference is made to the following description,taken together with the accompanying drawing, and its scope will bepointed out in the appended claims.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph showing the effect of pH and additives on the turnoverrate of Ni^(II) (salen)-catalyzed epoxidation of styrene.

DETAILED DESCRIPTION OF THE INVENTION The Macrocyclic Ring Compounds

The compounds represented by structure IA and IB are characterized bytheir ability to form stable complexes with transition metals Stablecomplexes are those having measurable lifetimes at room temperature inwater or common organic solvents.

The ability of IA and IB to form stable complexes results from therelative positions of the nitrogen atoms. The rest of the ring nucleusconsists of carbon atoms that may be thought of as collectively forminga scaffold for maintaining the proper position of the nitrogen atoms.

Substituents on the atoms of the ring nucleus affect the properties ofthe compounds, such as their solubility in various solvents and thestability of the complex they form with transition metals. The onlysubstituents that are critical to the present invention are L₁ and L₂.The ring carbon and nitrogen atoms other than the carbon atoms that bearL₁ and L₂ are normally substituted with sufficient hydrogen atoms toform a stable compound. It should be appreciated, however, that any ofthe positions, whether or not so indicated in IA and IB, may besubstituted with any other group and still do substantially the samething in substantially the same way to accomplish the same result andare, therefore, to be considered equivalent to positions bearinghydrogen atoms as substituents for the purpose of determining the scopeof the present invention.

For example, some of the positions shown in structures IA and IB do notappear to have substituents other than hydrogen. Nevertheless, eventhese positions may be substituted by any organic or inorganic groupwithout significantly affecting the ability of the compound to form acomplex with transition metals.

Accordingly, any one or more of these positions may be substituted by aninorganic substituent, such as a doubly bonded oxygen, i.e., carbonyl,or a singly bonded oxygen i.e., hydroxy. Some additional inorganicgroups include, for example, amino, thio, halo, i.e., F, Cl, Br, and I,etc.

Organic substituents include, for example, alkyl, aryl, alkylaryl andarylalkyl. The alkyl groups may be branched or unbranched and contain 20carbon atoms or less, preferably 8 carbon atoms or less, and morepreferably 4 carbon atoms or less. Some typical examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,tert-butyl, isobutyl, and octyl. The alkyl groups may, in whole or inpart, be in the form of rings such as cyclopentyl, cyclohexyl,cycloheptyl and cyclohexylmethyl. The cyclic groups described above maybe further substituted with inorganic, alkyl, or aryl groups. Any of thealkyl groups described above may have one or more double or triple bond.Moreover, any of the carbon atoms of the alkyl groups may be separatedfrom each other or from the ring nucleus with groups such as carbonyl,oxycarbonyl, oxy, amino, thio, etc. Alkyl groups may also terminate withgroups such as halo, hydroxy, amino, carboxy, etc.

Aryl substituents are typically phenyl, but may also be any other arylgroup such as, for example, pyrrolyl, furanyl, thiophenyl, pyridyl,thiazolyl, etc. The aryl group may, further, be substituted by aninorganic, alkyl, or other aryl group.

The alkylaryl and arylalkyl groups may be any combination of alkyl andaryl groups. These groups may be further substituted.

In structures IA and IB, n and m independently, represent 0 or 1 exceptthat n and m do not both represent 0. Accordingly, the macrocyclic ringnucleus of structures IA and IB has 13 or 14 members. The preferred ringsize depends on the diameter of the ion being complexed.

X₁, X₂, Z₁ and Z₂ independently represent two hydrogen atoms or a doublybonded oxygen atom. As mentioned above, either or both of the hydrogenatoms may be substituted by any inorganic or organic groups Preferably,X.sub. and X₂ both represent doubly bonded oxygen while Z₁ and Z₂represent two singly bonded hydrogen atoms i.e., H₂.

Y₁, Y₂, Y₃ and Y₄, independently represent hydrogen or any otherinorganic or organic group, especially a group that will stabilize acomplex with a transition metal cation For example, Y₁, Y₂, Y₃ and Y₄may, independently, represent alkyl, especially lower alkyl, i.e., C₁-C₄. A group that is particularly advantageous on the ring nitrogenatoms is CH₂ COOH, which tends to enhance the association of metal ionsto polyamine ligands.

L₁ and L₂ independently represent a group (L) derived from an alphaamino acid, LCH(NH₂)CO₂ H. The alpha amino acid may be naturallyoccurring or synthetic. Some examples of synthetic alpha amino acidsinclude, for example, phenylglycine (L₁ and/or L₂ =phenyl) and2-amino-3,3-dimethylbutanoic acid (L₁ and L₂ =tert-butyl). Some examplesof naturally occurring amino acids include, for example, those shown inthe table below:

    __________________________________________________________________________    Natural Amino Acids                                                           Amino Acid    Abbreviation                                                                          L.sub.1 and/or L.sub.2                                  __________________________________________________________________________    (+)-Alanine   Ala     CH.sub.3                                                (+)-Arginine  Arg                                                                                    ##STR8##                                               (-)-Asparagine                                                                              Asp(NH.sub.2)                                                                         H.sub.2 NCOCH.sub.2                                     (+)-Aspartic acid                                                                           Asp     HOOCCH.sub.2                                            (-)-Cysteine  CySH    HSCH.sub.2                                              (-)-Cystine   CySSCy                                                                                 ##STR9##                                               (+)-3,5-Dibromotyrosine                                                                              ##STR10##                                              (+)-3,5-Diiodotyrosine                                                                               ##STR11##                                              (+)-Glutamic acid                                                                           Glu     HOOCCH.sub.2 CH.sub.2                                   (+)-Glutamine Glu(NH.sub.2)                                                                         H.sub.2 NCOCH.sub.2 CH.sub.2                            Glycine       Gly     H                                                       (-)-Histidine His                                                                                    ##STR12##                                              (-)-Hydroxylysine                                                                           Hylys                                                                                  ##STR13##                                              (+)-Isoleucine                                                                              Ileu                                                                                   ##STR14##                                              (-)-Leucine   Leu     (CH.sub.3).sub.2 CHCH.sub.2                             (+)-Lysine    Lys     H.sub.2 NCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2            (-)-Methionine                                                                              Met     CH.sub.3 SCH.sub.2 CH.sub.2                             Ornithine             NH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2                     (-)-Phenylalanine                                                                           Phe                                                                                    ##STR15##                                              (-)-Serine    Ser     HOCH.sub.2                                              (-)-Threonine Thr                                                                                    ##STR16##                                              (+)-Thyroxine                                                                                        ##STR17##                                              (-)-Tryptophane                                                                             Try                                                                                    ##STR18##                                              (-)-Tyrosine  Tyr                                                                                    ##STR19##                                              (+)-Valine    Val     (CH.sub.3).sub.2 CH                                     __________________________________________________________________________

When the amino acid is hydroxyproline or proline, the polyazamacrocyclehas structure IB wherein R₁ and R₂ independently represent H or OH, andn, m, X₁, X₂, Z₁, Z₂, Y₃ and Y₄ have the same meaning as describedabove. The groups of the other natural amino acids have structure IA.

In order to benefit from the versatility of the L₁ and L₂ groups, L₁ andL₂ in the polyazamacrocycles of the present invention should not both beH. Preferably, when one of L₁ or L₂ is H, the other is not CH₃.

As will be shown below, compounds having the ring nucleus shown instructure IA and IB may be easily synthesized from amino acids. Thesynthesis does not affect the stereochemical integrity of the alphacarbon atoms of the amino acids, which, in nature, has the L or, inCahn-Ingold-Prelog terminology, S configuration. Accordingly, theconfiguration at positions 3 and 9 when m represents 1 and positions 3and 8 when m represents 0 is the same as that of the alpha carbon atomof the amino acid from which the macrocycle is made. In the case of anatural amino acid, these configurations are S, and structure IA maymore precisely be drawn as structure IC. ##STR20## wherein m, n, X₁, X₂,Y₁, Y₂, Y₃, Y₄, Z₁, Z₂, L₁ and L₂ have the same meaning as for structureIA.

It should be noted that the configuration of the alpha carbon atom ofthe amino acid used as the starting material does not change when theamino acid is converted to the corresponding macrocycle. The R or Sdesignation of the carbon atom in the macrocycle corresponding to thealpha carbon atom of the amino acid may change depending on the varioussubstituents in IC. Z₁ and Z₂ will be particularly influential in thisregard.

It should be further noted that where one or both of the amino acidsused as the starting compound is proline, l₁ and Y₁ and/or L₂ and Y₂ instructures IA and IC are joined together in a 5 membered ring. In thecase of hydroxyproline, the 3 position of the 5 member ring issubstituted with a hydroxy group.

The synthesis of the compounds having structure IA or IB may also startwith amino acids having the D (or R) configuration. Under thesecircumstances, the configuration of the carbon atoms at positions 3 and9 when m represents 1 and positions 3 and 8 when m represents 0 will beR (assuming Z₁ and Z₂ represent doubly bonded oxygen).

When positions 3 and 9 when m represents 1 and positions 3 and 8 when mrepresents 0 have the same configuration, L₁ and L₂ will be oriented inan anti fashion with respect to each other on the macrocyclic ring. Whenanti L₁ and L₂ groups are identical in IA and IB, the two faces of thering are equivalent and the molecule has C₂ symmetry.

The carbon atoms bearing L₁ and L₂ may also have differentconfigurations. This will occur when one of L₁ or L₂ is from an aminoacid with the S configuration while the other of L₁ or L₂ is from anamino acid with the R configuration. Under such circumstances thecompound will be a meso compound when L₁ and L₂ are identical.

The Complexes

The compounds of the present invention form stable complexes withtransition metal ions. For the purpose of this specification, transitionmetals are to be understood as including metals having partly filled dor f shells in any of their commonly occurring oxidation states.Accordingly, transition metals include the first transition series,which consists of Sc, Ti, V, Cr, Mn, Fe, Co, Ni, and Cu, as well as thesecond transition series, which consists of Y, Zr, Nb, Mo, Tc, Ru, Rh,Pd, and Ag. The transition metals in accordance with the abovedefinition further includes the lanthanide series, which consists of La,Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu, the thirdtransition series, which consists of Hf, Ta, W, Re, Os, Ir, Pt, and Au,and the actinide series, which consists of Ac, Th, Pa, U, Np, Pu, Am,Cm, Bk, Cf, Es, Fm, Md, No, and Lw. The most useful transition metalions are those of the first transition series, the second transitionseries, the lanthanide series and the third transition series.

The complexes are formed by contacting a salt of the metal ion with thepolyazamacrocycles in a suitable solvent such as, for example, water andmethanol. Progress of the complexation is easily followed visually orspectrophotometrically. Depending upon reaction conditions such as theligand, the metal, the pH, and the solvent, the complexation reactionmay occur rapidly at room temperature, or may require heating.

Some examples of metal ions capable of forming complexes in accordancewith the present invention include Ni²⁺, Co²⁺, Cu²⁺, Mn²⁺, and Gd³⁺,Pt²⁺ and Pd²⁺. Some examples of salts capable of forming such complexesinclude NiCl₂, Ni(OAc)₂, Cu(OAc₂), Pd(OAc)₂ and Pt(OAC)₂.

Under some conditions, the complex that is formed is deprotonated.Deprotonation is most likely to occur with hydrogens that are attachedto amido nitrogen atoms. Thus, deprotonation may occur in complexes ofstructure IA when Y₁ represents H and X₁ represents 0; when Y₂represents H and X₂ represents 0; when Y₃ represents H and Z₂ represents0; and when Y₄ represents H and Z₁ represents 0. For example, whennickel acetate is warmed with a compound having formula IA wherein n andm both represent 1; X₁ and X₂ both represent 0; Y₁, Y₂, Y₃, Y₄, Z₁ andZ₂ all represent H, the following complex is formed: ##STR21##

Complexes such as II between a doubly positive metal ion and adi-deprotonated ligand are particularly stable, since they are neutralmolecules. Such di-deprotonated complexes are particularly suitable forcatalyzing oxidation reactions of alkenes with oxidizing agents such ashypochlorite ion, since such di-deprotonated complexes are squareplanar. Square planar complexes are believed to be more effectiveoxidation catalysts than complexes having other geometries.

Utility

The compounds having formula IA and IB are useful in the sequestrationof transition metal ions. Therefore, these compounds may be used in thequalitative and quantitative assays of transition metal ions. (Forexample, see Kaden, Topics in Current Chemistry, 121, 157-180 (1984)).The complexes formed when compounds IA and IB sequester transition metalions are, further, useful in biomimetic catalysis (Kinneary et al.,Tetrahedron letters, 29, 877 (1988)) and in biomedical applications(Morphy et al., J. Chem. Soc., Chem. Commun., 156 (1988)).

Oxidations

The transition metal complexes of the present invention are particularlyuseful in the oxidation of alkenes to epoxides with a variety ofwater-soluble oxidizing agents under phase transfer conditions. Theoxidations may also utilize Schiff base complexes such as a salen or asalophen Salen complexes may be prepared using the method of Poddar etal., J. Indian Chem. Soc. 40, 489-490 (1963).

Some examples of oxidizing agents include peroxymonosulfate salts andhypochlorite salts. The preferred peroxymonosulfate salt is potassiumperoxymonosulfate, which is commercially available under the trademarkOXONE. Some examples of hypochlorite salts include lithium, sodium andpotassium hypochlorite. Any transition metal capable of catalyzing theoxidation may be used in the complex. The complexes of Ni²⁺, Cu²⁺, Co²⁺,Pd²⁺ and Pt²⁺ are preferred. Ni²⁺ is especialy preferred.

The oxidizing agent is dissolved in water and the alkene to be oxidizedis dissolved in a suitable organic H solvent, for example, CH₂ Cl₂,CHCl₃ or toluene. A phase transfer catalyst is added to the system inorder to deliver the water soluble oxidizing agent into the organicphase.

The complexes of the present invention are particularly suitable forcatalyzing oxidation reactions under such conditions, since complexeshaving various L₁ and L₂ groups may easily be synthesized (see below).Having a large selection of various L₁ and L₂ groups providesflexibility in tailoring an oxidation catalyst with the rightsolubilities in the two phases The temperature at which the oxidationreaction is conducted is not critical, and may conveniently be variedbetween 0° C. and the boiling point of the organic solvent. Preferably,the reaction may be conducted at room temperature. The progress of thereaction may be monitored by chromatography or spectrophotometry.

The rate of oxidation is dramatically influenced by the pH. Lowering thepH accelerates the epoxidations. The pH of the reaction may vary fromabout 6 to about 14, more preferably below 12.5 and most preferablybetween 9 and 10.5 when hypochlorite is the oxidizing agent and between6 and 9, preferably between 7 and 8 when peroxymonosulfate is theoxidizing agent. On an overall basis, pH ranges may be described as fromabout 6 to about 12.9, with 8.5 to 12 preferred and 8 to 11 mostpreferred. The rate of oxidation and product yield are influenced by thepH and also by the presence of weak organic acids soluble in the organicphase, for example uncomplexed Schiff bases and certainsalicylaldehydes. Other useful weak acids are, for example, phenolswhich are more soluble in dichloromethane than in water and which havepK_(a) values less than about 8. The organic acid may be added in anamount of from about 0.001 to about 0.5 moles of organic acid per moleof alkene, preferably from about 0.003 to about 0.05. The concentrationof the alkene is not critical and may vary between wide limits. Forexample, the reaction may conveniently be conducted in an alkeneconcentration between 0.01 and 1M, preferably between 0.2 and 0.6M.

The concentration of the hypochlorite salt in the aqueous phase is alsonot critical and depends in part upon the concentration of the alkeneconcentration in the organic phase. The ratio of equivalents ofhypochlorite ion to alkene may vary between 2:1 and 10:1, preferablybetween 4:1 and 5:1. Preferably the hypochlorite is slowly added to thereaction mixture at a rate of from about 0.01 to about 10 equivalents ofhypochlorite ion per alkene equivalent per minute, more preferably 0.4to 2 equivalents per minute.

The ratio of equivalents of the transition metal complex to that of thealkene substrate is also not critical, and may vary between, forexample, 1:10 and 1:10,000, preferably between 1:100 and 1:4000.

Some suitable phase transfer catalysts include, for example,benzyltrimethylammonium salts, such as the halides, and especially thebromide. The concentration of the phase transfer catalyst is also notcritical and may vary widely Some suitable phase transfer catalystconcentrations include 0.005-0.05M, preferably 0.01-0.03M.

II a-d were prepared in order to test various complexes as catalystsunder phase transfer conditions:

a:L₁ and L₂ =CH₂ Ph

b:L₁ and L₂ =CH₂ CH(CH₃)₂

c:L₁ and L₂ =CH(CH₃)₂

d:L₁ and L₂ =H Standard reaction conditions involved treatment withvigorous stirring of 1.7 mmol trans-beta-methylstyrene, 0.04 mmol of theappropriate Ni²⁺ catalyst (IIa-d) and 0.08 mmol PhCH₂ NMe₃ ⁺ Br⁻ (phasetransfer catalyst) dissolved in 5 ml CH₂ Cl₂ with 10 ml 0.77M aqueousNaOCl (pH 12-13). Reactions were carried out at room temperature.Periodically removed aliquots of the organic layer were monitored by gaschromatography. The yields of oxidation products obtained are listed inTable I below.

                  TABLE I                                                         ______________________________________                                        Percent Product Yields from Oxidation of                                      trans-beta-Methylstyrene with NaOCl                                           Catalyzed by Ni.sup.II Complexes..sup.1,2                                            recovered                                                              catalyst                                                                             starting material                                                                             epoxide  benzaldehyde                                  ______________________________________                                        II (a)  0              51       23                                            II (b) 49              26       9                                             II (c) 96               1       2                                             II (d) 87               2       6                                             ______________________________________                                         .sup.1 Yields based on initial alkene conc.; balance is sodium benzoate.      .sup.2 Reaction conditions: 1.7 mmol alkene, 0.04 mmol Ni.sup.II catalyst     0.08 mmol PhCH.sub.2 NMe.sub.3.sup.+ Br.sup.-  in 5 mL CH.sub.2 Cl.sub.2      and 10 mL 0.77M NaOCl in water at room temperature.                      

The rate of epoxidation is accelerated and epoxidation product yieldsare increased by lowering the pH of the aqueous phase. While at pH 12.5epoxidation requires 4-5 hours for 20-40 turnovers of catalyst, when thepH is lowered below 12.5, over 20 turnovers to give epoxide can beachieved in 15 minutes.

Similarly, the addition of certain organic phase soluble weak organicacids such as salen or ortho- or para- salicylaldehydes increases thereaction rate. A combination of both lowering the pH and the addition ofweak organic acid leads to an even higher reaction rate. In typicalreaction conditions, a solution of 4 mmol alkene, 0.15 mmolbenzyltributylammonium bromide and 0.001-0.1 mmol nickel catalyst in 10mL CH₂ Cl₂ are stirred at room temperature with 20 mL 0.77 M NaOCladjusted to pH 9.3 using a buffer such as borate buffer. In one set ofexperiments, Gas chromotography analysis gave the results listed inTable II:

                                      TABLE II                                    __________________________________________________________________________    Turnover Numbers and Selectivity of Alkene                                    epoxidation at Lowered pH Using HOCl and Ni.sup.II Catalysts                                                epoxide                                            catalyst                                                                              salen          conv..sup.c                                                                       select..sup.d                                                                     turnover no.                                entry                                                                            (mol %).sup.a                                                                      pH mol %.sup.b                                                                        substrate %   %   min.sup.-1                                  __________________________________________________________________________    1  1 (2.5)                                                                            12.5                                                                             0    norbornene                                                                               94 32   0.040                                      2  1 (2.5)                                                                            9.3                                                                              7.5  norbornene                                                                              100 23  1.8                                         3  1 (2.5)                                                                            12.5                                                                             0    E-PhCH═CHCH.sub.3                                                                   100 89  0.15                                        4  1 (0.063)                                                                          9.3                                                                              1.5  E-PhCH═CHCH.sub.3                                                                   100 60  192                                         5  1 (0.013)                                                                          9.3                                                                              0.3  E-PhCH═CHCH.sub.3                                                                   100 27  432                                         6  1 (0.013).sup.e                                                                    9.3                                                                              0.3  E-PhCH═CHCH.sub.3                                                                    63 76  640                                         7  2 (1.0)                                                                            12.5                                                                             .sup.f                                                                             E-PhCH═CHCH.sub.3                                                                    30 53   0.047                                      8  2 (1.0)                                                                            9.3                                                                              .sup.f                                                                             E-PhCH═CHCH.sub.3                                                                   100 45  9.0                                         9  2 (2.5)                                                                            12.5                                                                             .sup.f                                                                             cyclohexene                                                                             100 13  0.17                                        10 2 (2.5)                                                                            9.3                                                                              .sup.f                                                                             cyclohexene                                                                             100 16  0.21                                        __________________________________________________________________________     .sup.a (Moles catalyst/moles alkene) × 100.                             .sup.b (Moles additional salen/moles alkene) × 100.                     .sup.c Disappearance of alkene.                                               .sup.d Epoxide/total products.                                                .sup.e Slow addition of NaOCl at rate of 1 equiv. NaOCl per alkene equiv.     per min.                                                                      .sup.f Additives such as salicylaldehyde had a small effect on the            reaction.                                                                     Catalyst 1 was Ni(salen) (structure 4).                                       Catalyst 2 was catalyst II(a).                                           

As can be seen from Table II, entry 6, at pH 9.3 with the addition ofsalen and slow addition of OCl⁻, an alkene substrate can be epoxidizedat a rate of at least 640 turnovers in one minute.

The data from the epoxidations of Table II is summarized in FIG. 1showing the effect of pH and additives on turnover rate of Ni^(II)(salen)-catalyzed epoxidation of styrene using 2.5 mol % catalyst. Curve(A) is at pH 12.5 with no additives. Curve (B) is at pH 12.5 with 7.5mol % salen added. Curve (C) is at pH 9.3 (borate buffer) with noadditives. Curve (D) is at pH 9.3 (borate buffer) with 7.5 mol % salenadded.

Catalysts II (a-d) may be prepared in accordance with the methoddescribed below starting from L-phenylalanine, L-leucine, L-valine andglycine, respectively. This synthetic pathway preserves thestereochemistry of the alpha carbon atom of the amino acid, whichultimately becomes the carbon atom at the 3 and 9 position of the 14member ring and at the 3 and 8 positions of the 13 member ring. When L₁and L₂ groups and the groups on the double bond of the alkene aresufficiently bulky, asymmetric induction will occur, and the resultingepoxide is chiral This is not the case, however, fortrans-beta-methylstyrene and any of catalyst complexes II a-d. Noasymmetric induction occurred during these reactions under theconditions described above. (Catalyst IId is also commercially availablefrom Aldrich Chemical Company.)

The most efficient catalysis occurred in the presence of IIa derivedfrom phenylalanine. After 6.5 hours, all of the alkene was consumed, andtwo types of reaction products were formed. About half of themethylstyrene was converted to the corresponding epoxide. The other halfof the methylstyrene underwent C═C bond cleavage to produce benzaldehydeand, presumably, acetaldehyde, which was not detected under theconditions of analysis. Since benzaldehyde is slowly oxidized by basichypochlorite to water-soluble benzoate, analysis of the CH₂ Cl₂ layerprovided reliable data only for the determination of disappearance ofstarting material and appearance of epoxide. Relative amounts of PhCHOand PhCO₂ H were variable.

Synthesis of Compounds

Compounds IA and IB may be prepared by various methods. Scheme I shows aconvenient and general synthesis for forming IIa, which is the nickelcomplex of structure IA wherein m and n represent 1; X₁ and X₂ representoxygen; Y₁ , Y₂, Y₃ and Y₄ represent hydrogen; Z₁ and Z₂ represent twosingle bonded hydrogen atoms and L₁ and L₂ represent benzyl. Thestarting material in Scheme I is phenylalanine.

In the first step of Scheme I, the amino group of phenylalanine isprotected with a protecting group, and the carboxyl group is activatedby conversion to an ester (III). Some examples of protecting groupsinclude, for example, carbobenzyloxy (cbz) and tertiary-butyloxycarbonyl(t-boc). Some examples of activated esters include, for example, theN-hydroxysuccinimide and aryl esters. ##STR22##

Compound III is condensed with at least 0.5 equivalents of1,3-diaminopropane in a suitable solvent to form protected diamide IV.Some suitable solvents include, for example, DME, DMF, THF, and dioxane.The carbobenzyloxy group is removed by catalytic hydrogenolysis with,for example, palladium on activated carbon in a suitable solvent suchas, for example, acetic acid, methyl alcohol or ethyl alcohol, or byhydrolysis with HF, HCl, or HBr.

The resulting diamide V is reduced to tetraamine VI. Some suitablereducing agents for converting diamide V to tetraamine VI include, forexample, borane/THF, and lithium aluminum hydride.

Tetraamine VI is treated with dimethyl or diethyl malonate or malonyldichloride under suitable conditions, such as, for example, refluxingmethyl alcohol for five days to form dioxocyclam VII.

It is readily apparent that Scheme I may be modified in order to produceother compounds of IA and IB. For example, compounds wherein Z₁ and Z₂represent two singly bonded hydrogen atoms may be prepared byeliminating the step in which diamide V is reduced to tetraamine VI.Compounds wherein m represents 0 may be prepared by treating diamine VIwith dimethyl oxalate or oxalyl dichloride. Compounds where n represents0 may be prepared by treating ester III with 1,2-diaminoethane insteadof 1,3-diaminopropane. Compounds wherein X₁ and X₂ both represent twosingly bonded hydrogen atoms may be prepared by reduction of diamide VIIwith, for example, borane/THF. Compounds wherein Y₁ and Y₂ independentlyrepresent lower alkyl or carboxymethyl may be prepared by starting withone or more amino acids wherein the amino group is substituted with analkyl or carboxymethyl group.

Alternatively, Y₁ , Y₂, Y₃ and/or Y₄ that represent H and are on anamino, as opposed to an amido, nitrogen atom may be converted to Y₁ ,Y₂, Y₃ and/or Y₄ that represent lower alkyl or carboxymethyl bytreatment with an appropriate alkylating agent such as, for example, analkyl halide, expecially an alkyl bromide or iodide, or a haloaceticacid, especially bromoacetic acid. Approriate protecting groups may beemployed where required.

Compounds wherein Y₃ and Y₄ represent lower alkyl or carboxymethylgroups may be prepared by treating ester III with 1,3-diaminopropanewherein the amino groups are substituted with a lower alkyl orcarboxymethyl group. Compounds having configurations other than the SSconfiguration at carbon atoms 3 and 9 of compound IA wherein m and nrepresent 1 and positions 3 and 8 wherein m represents 0 and nrepresents 1 may be prepared by starting with amino acids having the D(i.e. R) configuration.

The tetraamide and tetraamine intermediates obtained prior to formingthe macrocyclic ring with oxalic or maleic acid derivatives (i.e., IV, Vand VI) are useful not only as intermediates for forming the macrocycliccompounds of the present invention, but also as transition metal ioncomplexing agents. These compounds may be generally represented asfollows: ##STR23## wherein Y₁, Y₂, L₁, L₂, Z₁, Z₂, Y₃, Y₄, R₁, R₂, and nall have the meanings described above and E₁ and E₂ represent H or aprotecting group.

EXAMPLES General Procedure for N-carbobenzyloxy-L-amino acidN-hydroxysuccinimide esters (III):

L-alpha-amino acids were converted to their Cbz analogs according toprior art procedures (Ramage et al., J. Chem. Soc., Perkin 1, 461-470(1985)). These products were then treated with N-hydroxysuccinimide byknown procedures to produce compound III (Anderson et al., J. Am. Chem.Soc., 86, 1839-1842 (1964)].

N,N'-Bis-(N-carbobenzyloxy-L-phenylalanyl)-1,3-diaminopropane (IVa)

Compound IIIa (2.52 g, 6.4 mmol) was dissolved in anhydrousdimethyoxyethane (DME) (100 mL), cooled to 0° in an ice bath, and1,3-diaminopropane (0.27 mL, 3.20 mmol) was added dropwise The reactionmixture was allowed to warm to room temperature for 18 hours. The whiteprecipitate that formed was collected to vacuum filtration, and thesolid material was washed with small portions of cold H₂ O followed bycold MeOH. The final product was stored in a vacuum desiccatorcontaining P₂ O₅. Yield, 198 g (98%); mp 226°-227° C.

N,N'-Bis-(N-carbobenzyloxy-L-leucyl)-1,3-diaminopropane (IVb)

In a procedure similar to that described above for the synthesis of IVa,IIIb (11.60 g, 0.032 mol) was treated with 1,3-diaminopropane (1.19 g,0.016 mol) to yield IVb as a white solid which was recrystallized frommethanol to produce fine white crystals Yield 8.01 g (88%); mp 177°-178°C.

N,N'-Bis-(N-carbobenzyloxy-L-valyl)-1,3-diaminopropane (IVC)

In a procedure similar to that described for IVa, IIIc (16.51 g, 0.047mol) was treated with 1,3-diaminopropane (1 74 g, 0.024 mol) to yieldIVc as a white solid recrystallized from isopropanol Yield, 10.62 g(83%); mp 211°-212° C.

N,N'-Bis(phenylalanyl)-1,3-diaminopropane (Va)

Compound IVa (3.00 g, 4.72 mmol) was suspended in 200 mL MeOH. 5% Pd onactivated carbon (0.35g) was added and the mixture was degassed (bysuccessive evacuation and venting to hydrogen) and treated with H₂ (40PSI) for 15 hours. The resulting solution was filtered through celite,washed several times with MeOH and concentrated to give a clearcolorless oil. Trituration with diethylether resulted in the formationof IVa as a white solid.

N,N'-Bis-(leucyl)-1,3-diaminopropane (Vb)

In a procedure similar to that described for Va, compound IVb (3.07 g,5.40 mmol) was subjected to hydrogenolysis to produce Vb as a slightlyyellow semi-solid. Yield 1.60 g (98.6%).

N,N'-Bis-(valyl)-1,3-diaminopropane (Vc)

In a procedure analogous to that described for the preparation of Va,compound IVc (2.97 g, 5.50 mmol) was subjected to hydrogenolysis toproduce Vc as a clear colorless oil. Yield, 1.46 g (98%).

(2S,10S)-2,10-dibenzyl-1,4,8,11-tetraazaundecane tetrahydrochloride(VIa.4HCl)

A 1M BH₃ /THF solution (67 ml, 0.067 mol) was added dropwise over a 1hour period to a cooled (0° C.) solution of Va (4.1 g, 11.1 mmol) inanhydrous THF (100 mL). After addition was complete, the solution wasallowed to warm to room temperature for 1 hour followed by heating toreflux for an additional 18 hours. The resulting solution was cooled,and the excess diborane was quenched by the dropwise addition of a 10%HSO/THF solution. The solvent was removed in vacuo, and 6M HCl (100 ml)was added to the residue and heated to reflux for 1 hour. After cooling,the solution was concentrated to a white semi-solid. A 4M NaOH solution(40 ml) was added, and the solution was extracted 4 times with 100 mlportions of CHCl₃. The organic layers were combined, dried (Na₂ SO₄),filtered, and concentrated to give a yellow oil, which was subsequentlydissolved in absolute EtOH (75 ml). HCl gas was passed through the EtOHsolution. The resulting white precipitate that formed was collected byvacuum filtration and washed with cold EtOH. Yield, 5.3 g (83%), mp243°-245° C. (dec.).

(2S, 10S)-2,10-di(iso-butyl)-1,4,8,11-tetraazaundecanetetrahydrochloride (VIb 4HCl)

In a procedure similar to that described above, compound Vb (1.44 g,5.30 mmol) was treated with 6 equiv. BH₃ /THF. After the normal work-up,the tetrahydrochloride salt of VIb was isolated as a white powder.Yield, 2.08 g (93%).

(2S,10S)-2,10-diisopropyl-1,4.8,11-tetraazaundecane tetrahydrochloride(VIc 4HCl)

In a procedure similar to that described above, compound Vc (1.40 g,5.14 mmol) was treated with 6 equiv BH₃ /THF. The normal work-upproduced the tetrahydrochloride salt of VIc as a white solid. Yield, 150 g (75%), mp>260° C.

(3S,9S)-3,9-Dibenzyl-1,4,8.11-tetraazacyclotetradecane-5,7-dione (VIIa))

Compound VI(a) (1.02 g, 2.9 mmol) and dimethyl malonate (0.47 g, 2.90mmol) were heated at reflux in anhydrous MeOH (100 mL) for 5 days. Aftercooling, the reaction mixture was concentrated to a yellow oil which wasthen triturated with diethyl ether, resulting in the formation of anoff-white solid. Further purification of the solid material by columnchromatography on silica gel (15% MeOH/CHCl₃) led to the isolation ofVII(a) as a white solid. Yield, 70.8 mg, (8%) mp 235°-237° C. (dec)

(3S,9S)-3,9-Dibenzyl-1,4,8,11-tetraazacyclotetradecane-5,7-dione]nickel.sup.II(IC(b)

Following the general procedure given for VII(a), compound VI(b) (39.8mg, 0.117 mmol) was treated with Ni(OAc)₂ (30 mg, 0.12 mmol) to give theyellow complex IIb. Yield, 32 mg (70%).

(3S,9S)-3,9-isopropoyl-1,4,8,11-tetraazacyclotetradecane-5,7-dione]nickel.sup.II(IC(c))

Following the general procedure described for IIb, compound ID(c) (32mg, 0.102 mmol) was treated with Ni(OAc)₂ (25 mg, 0.100 mmol) to giveIIc as a yellow solid. Yield, 33 mg, (88%).

General Procedure For First Oxidation Studies

In a typical experiment 1.7 mmol trans-betamethylstyrene, 0.04 mmol ofthe appropriate Ni^(II) catalyst (IIa-d) and 0.08 mmol PhCH₂ NME₃ ⁺ Br⁻(phase transfer catalyst) were dissolved in 5 mL CH₂ Cl₂ and stirredvigorously with 10 mL 0.77M aqueous NaOCl (pH 12-13). Aliquots of theorganic layer were periodically removed, passed through a short columnof neutral alumina, and analyzed for oxidation products by gaschromatography using a 5% phenyl methyl silicone capillary column(10m×.53mm) with PhBr as an internal standard.

General Procedure For Second Oxidation Studies: Epoxidation withControlled pH.

Norbornene, trans-B-methylstyrene and cyclohexene were individuallyreacted in a solution of 4 mmol alkene, 0.15 mmol benzyltributylammoniumbromide as a phase transfer catalyst and 0.001-0.1 mmol nickel salen ornickel dioxocyclam catalyst in 10 mL CH₂ Cl₂. The mixture was stirred atroom temperature with 20 mL 0.77M NaOCl at pH 12.5 or adjusted to pH 9.3with borate buffer. In test mixtures 2, 4, 5 and 6 additional salen wasadded in amounts of 7.5, 1.5, 0.3 or 0.3 respectively mole percent permole of alkene substrate. Salicylaldehyde was added to test mixtures 7,8, 9 and 10. In test mixture 6, NaOCl was slowly added at a rate of 1equiv. NaOCl per alkene equivalent per minute. Gas chromotographyanalysis was undertaken using a dichlorobenzene as an internal standard.The results are shown above in Table II.

Epoxidation Control Studies

Control studies were carried out to insure that the reaction ismetal-dependent, independent of other oxidants such as O₂, and that theepoxidation occurs only in the organic phase. In a transport-typeexperiment, two CH₂ Cl₂ solutions containing alkene and phase transfercatalyst were connected by an aqueous NaOCl solution Epoxidationoccurred only in one CH₂ Cl₂ solution which also contained Ni^(II)(salen).

In another experiment, Alkene and Ni^(II)(salen) were added to asolution of anhydrous Bu₄ N⁺ OCl⁻ in CH₂ Cl₂. No epoxide was formedafter 30 min.; however, additional of excess benzoic acid led to 26turnovers of epoxide It was concluded that HOCl rather than OCl⁻ is thereactive oxidant with Ni^(II) catalyst

While there have been described what are presently believed to be thepreferred embodiments of the invention, those skilled in the art willrealize that changes and modifications may be made thereto withoutdeparting from the spirit of the invention and it is intended to claimall such changes and modifications as falling within the true scope ofthe invention.

What is claimed is:
 1. A method for oxidizing alkenes to epoxidescomprising treating the alkene with a transition-metal ion-square planarcomplex, the square planar complex selected from the group consisting ofa 13 or 14 member macrocyclic compound having the ring nucleus ##STR24##n=O or 1; m=O or 1;n+m>O; ' X₁, X₂, Z₁ and Z₂ independently represent H₂or O; Y₁, Y₂, Y₃ and Y₄ independently represent H, lower alkyl or CH₂COOH; and L₁ and L₂ independently represent side chains of alpha aminoacids, except that L₁ and L₂ do not both represent H; and R₁ and R₂independently represent H or OH; and peroxymonosulfate ion orhypochlorite ion in a two phase system comprising a phase transfercatalyst, an aqueous phase having a pH from about 6 up to 12.9 and anorganic solvent phase in which the complex is soluble.
 2. The method ofclaim 1 wherein the metal ion is Ni²⁺, Cu²⁺, Co²⁺, Pd²⁺ or Pt²⁺.
 3. Themethod of claim 1 wherein the metal ion is Ni²⁺.
 4. The method of claim1 wherein the two phase system further comprises a soluble weak acid. 5.The method of claim 4 wherein the soluble weak acid is a phenol which ismore soluble in organic solvents than in water and which as a pK_(a)less than about
 8. 6. The method of claim 4 wherein the weak solubleacid is selected from the group consisting of salens, ortho- and para-salicylaldehyde.
 7. The method of claim 4 wherein the soluble weak acidis added in an amount of from about 0.001 to about 0.5 moles of solubleweak acid per mole of alkene.
 8. The method of claim 1 wherein theperoxymonosulfate or hypochlorite is added to the two phase system at aslow rate of about 0.01 to about 10 equivalents of oxidizing agent peralkene equivalent per minute.
 9. The method of claim 1 wherein the ratioof equivalents of transition metal ion--square planar complex to that ofalkene substrate is from about 1:10 to about 1:10,000.
 10. The method ofclaim 1 wherein the pH of the aqueous phase is from about 7 to about 12.